CN112574132B - Preparation method of sarcandra/valsartan sodium - Google Patents
Preparation method of sarcandra/valsartan sodium Download PDFInfo
- Publication number
- CN112574132B CN112574132B CN201910942858.2A CN201910942858A CN112574132B CN 112574132 B CN112574132 B CN 112574132B CN 201910942858 A CN201910942858 A CN 201910942858A CN 112574132 B CN112574132 B CN 112574132B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- sac01
- bpa08
- sac02
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 241000736026 Sarcandra Species 0.000 title abstract description 5
- NQRAWXHLZGWKRS-FTBISJDPSA-N [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 Chemical compound [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 NQRAWXHLZGWKRS-FTBISJDPSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 234
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 84
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 40
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 230000008569 process Effects 0.000 claims abstract description 16
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 15
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000001110 calcium chloride Substances 0.000 claims abstract description 10
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 139
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 229940011051 isopropyl acetate Drugs 0.000 claims description 23
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000000746 purification Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 4
- 229960004699 valsartan Drugs 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 230000003321 amplification Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 62
- 239000003153 chemical reaction reagent Substances 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 229910052742 iron Inorganic materials 0.000 description 12
- 229910052707 ruthenium Inorganic materials 0.000 description 12
- 238000004821 distillation Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000005070 sampling Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- 229910006124 SOCl2 Inorganic materials 0.000 description 4
- 238000000105 evaporative light scattering detection Methods 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000010812 external standard method Methods 0.000 description 3
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- -1 1H-tetrazol-5-yl Chemical group 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 229940100321 entresto Drugs 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- MWZPENIJLUWBSY-SECBINFHSA-N methyl (2r)-2-amino-3-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-SECBINFHSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HQAITFAUVZBHNB-UHFFFAOYSA-N sodium;pentahydrate Chemical compound O.O.O.O.O.[Na] HQAITFAUVZBHNB-UHFFFAOYSA-N 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of sarcandra, which belongs to the field of medicinal chemistry, wherein compound S309A03 is used as a raw material, compound BPA08 is generated through hydrogenation reaction, compound BPA08 is reacted in ethanol to generate compound SAC01, compound SAC01 is reacted with succinic anhydride to generate compound SAC02, optionally, compound SAC02 is reacted with sodium hydroxide to generate compound SAC03, and compound SAC03 is reacted with calcium chloride to generate compound SAC04; compound SAC04 is treated with acid to obtain compound YJX01, and the compound YJX01 is reacted with VST in a single solvent in the presence of sodium hydroxide to obtain compound YJX02. The preparation method disclosed by the invention is simple to operate, reduces the time required by the process, greatly improves the total yield of the process route, and obtains unexpected technical effects. The process condition is mild, the raw materials are easy to obtain, and the method is suitable for industrial amplification.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a sarcandra-containing intermediate and a preparation method thereof.
Background
Sarcandesartan sodium, also known as LCZ696 (trade name: entresto), is a dual-effect angiotensin receptor enkephalinase inhibitor developed by Novartis, inc., and has a unique mode of action and is believed to be capable of reducing the strain of a failing heart. The drug was FDA approved at month 7 of 2015. The chemical name of the catalyst is hexa (4- { [ (1S, 3R) -1- ([ 1,1' -biphenyl ] -4-methyl) -4-ethoxy-3-methyl-4-oxobutyl ] amino } -4-oxobutanoic acid) hexa (N-pentanoyl-N- { [2' - (1H-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl ] methyl } -L-valine) -octadecanoic sodium salt pentahydrate.
LCZ696 has the structural formula:
U.S. patent No. 5217996 discloses a preparation method of an intermediate compound of LCZ696, but the method uses expensive (D) -4-hydroxyphenylalanine methyl ester as a raw material, palladium-carbon is used as a catalyst for reduction of carbon-carbon double bonds in the last step, the stereoselective behavior is 80:20, and the compound VII with higher purity can be obtained after recrystallization, but the yield loss is larger. The method has longer steps and higher production cost.
Patent documents such as CN101098689A and CN102702119A, CN106397248A adopt mixed solvents of isopropyl acetate and acetone or IPA and acetone and the like in the synthesis process of LCZ696, and adopt a composite solvent, so that inconvenience is brought to solvent recovery; CN104557600a, CN105168205A, yields obtained from the process for preparing LCZ696 or intermediate compounds are low.
In view of the good market for LCZ-696 itself and the shortcomings of existing synthetic methods, it would be highly desirable to develop new synthetic processes for LCZ-696 or key intermediates thereof.
Disclosure of Invention
The invention provides a preparation method of sarcandra sodium, which takes compound S309A03 as a raw material, and generates compound BPA08 through hydrogenation reaction, compound BPA08 reacts in ethanol to generate compound SAC01, compound SAC01 reacts with succinic anhydride to generate compound SAC02, compound SAC02 reacts with sodium hydroxide to generate compound SAC03, and compound SAC03 reacts with calcium chloride to generate compound SAC04; compound SAC04 is treated with acid to obtain compound YJX01, and the compound YJX01 is reacted with VST in a first solvent and in the presence of sodium hydroxide to obtain compound YJX02.
In a first aspect, the preparation method of the sarcandesartan sodium provided by the invention comprises a preparation method of a compound SAC04.
A method for preparing compound SAC04, comprising at least one of the following reactions:
the compound S309A03 generates a compound BPA08 through hydrogenation, the compound BPA08 generates a compound SAC01 through reaction in ethanol, the compound SAC01 generates a compound SAC02 through reaction with succinic anhydride, the compound SAC02 generates a compound SAC03 through reaction with sodium hydroxide, and the compound SAC03 generates a compound SAC04 through reaction with calcium chloride; wherein, at least one of the compound BPA08, the compound SAC01, the compound SAC02 and the compound SAC03 generated by the reaction is directly used for the next reaction without purification and/or drying.
In some embodiments, a method of preparing compound SAC04 comprises: the compound S309A03 is hydrogenated to form a compound BPA08, and the compound BPA08 is reacted in ethanol to form a compound SAC01, wherein at least one of the compound BPA08 and the compound SAC01 formed by the reaction is directly used for the next reaction without purification and/or drying.
In some embodiments, a method of preparing compound SAC04 comprises: compound S309a03 is reacted by hydrogenation to produce compound BPA08 and compound BPA08 is reacted in ethanol to produce compound SAC01; optionally, further comprising: compound SAC01 reacts with succinic anhydride to produce compound SAC02, and/or compound SAC02 reacts with sodium hydroxide to produce compound SAC03, and/or compound SAC03 reacts with calcium chloride to produce compound SAC04.
In some embodiments, a method of preparing compound SAC04 comprises: the compound S309A03 is hydrogenated to generate a compound BPA08, and the compound BPA08 is reacted in ethanol to generate a compound SAC01, wherein at least one of the compound BPA08 and the compound SAC01 generated by the reaction is directly used for the next reaction without purification and/or drying; optionally, further comprising: compound SAC01 reacts with succinic anhydride to produce compound SAC02, and/or compound SAC02 reacts with sodium hydroxide to produce compound SAC03, and/or compound SAC03 reacts with calcium chloride to produce compound SAC04.
In some embodiments, a method of preparing compound SAC04 comprises: the compound S309A03 generates a compound BPA08 through hydrogenation, the compound BPA08 generates a compound SAC01 through reaction in ethanol, the compound SAC01 generates a compound SAC02 through reaction with succinic anhydride, the compound SAC02 generates a compound SAC03 through reaction with sodium hydroxide, and the compound SAC03 generates a compound SAC04 through reaction with calcium chloride; wherein, at least one of the compound BPA08, the compound SAC01, the compound SAC02 and the compound SAC03 generated by the reaction is directly used for the next reaction without purification and/or drying; this operation is advantageous in simplifying the process and steps and in obtaining the compound SAC04 in high yield. In some embodiments, at least one of compound BPA08 and compound SAC01 produced by the reaction is used directly in the next reaction without purification and/or drying; is beneficial to simplifying the process and steps and obtaining the compound SAC04 with high yield. In some embodiments, two of compound BPA08, compound SAC01, compound SAC02, and compound SAC03 produced by the reaction are used directly in the next reaction without purification and/or drying. In some embodiments, three of compound BPA08, compound SAC01, compound SAC02, and compound SAC03 produced by the reaction are used directly in the next reaction without purification and/or drying. In some embodiments, the compounds BPA08, SAC01, SAC02 and SAC03 produced by the reaction are used directly in the next reaction without purification and/or drying. In some embodiments, the compound BPA08 and compound SAC01 produced by the reaction are directly used in the next reaction without purification and/or drying, which is advantageous in simplifying the process and steps and obtaining compound SAC04 in high yield.
In some embodiments, the compound SAC01 is reacted with succinic anhydride, wherein the ethanol content of the solution of compound SAC01 is 0.5% -10%. The presence of ethanol is beneficial to removing impurities generated by the reaction; in some embodiments, the presence of ethanol facilitates removal of the following impurities:
in some embodiments, the compound SAC01 is reacted with succinic anhydride, wherein the ethanol content of the solution of compound SAC01 is 1% -8%.
In some embodiments, the solvent for the hydrogenation reaction is ethanol. Is beneficial to obtaining the compound BPA08 with higher purity.
In some embodiments, the reaction temperature of the hydrogenation reaction is from 45 ℃ to 100 ℃.
In some embodiments, the reaction temperature of the hydrogenation reaction is from 65 ℃ to 80 ℃.
In some embodiments, the solvent in which the compound SAC01 reacts with succinic anhydride is at least one of isopropyl acetate, methylene chloride, toluene, ethyl acetate, methyltetrahydrofuran, butyl acetate, t-butyl acetate, methyl t-butyl ether. The method is favorable for obtaining the compound SAC02 with higher purity, the reagent is easy to obtain, the reaction cost is low, and the reaction yield is favorable for being improved.
In some embodiments, the temperature at which the compound SAC01 reacts with succinic anhydride is 30 ℃ to 80 ℃. The reaction condition is mild, and the process cost is low.
In some embodiments, the temperature at which the compound SAC01 reacts with succinic anhydride is 50 ℃ to 60 ℃.
In some embodiments, the solvent in which the compound SAC02 reacts with sodium hydroxide is at least one of isopropyl acetate, methylene chloride, toluene, ethyl acetate, methyltetrahydrofuran, butyl acetate, t-butyl acetate, methyl t-butyl ether.
In some embodiments, the temperature at which the compound SAC02 reacts with sodium hydroxide is 0 ℃ to 10 ℃.
In some embodiments, the pH of the reaction solution of the compound SAC02 with sodium hydroxide is 7.0-8.0. Adjusting the appropriate pH facilitates better access to compound SAC03.
In some embodiments, the solvent in which the compound SAC03 reacts with calcium chloride is at least one of isopropyl acetate, methylene chloride, toluene, ethyl acetate, methyltetrahydrofuran, butyl acetate, t-butyl acetate, methyl t-butyl ether.
In some embodiments, the temperature at which the compound SAC03 reacts with calcium chloride is 80 ℃ to 120 ℃.
In some embodiments, the temperature at which the compound SAC03 reacts with calcium chloride is 60 ℃ to 100 ℃.
In a second aspect, the invention provides a preparation method of sarcandesartan sodium, which comprises a preparation method of a compound YJX02 (sarcandesartan sodium).
A preparation method of a compound YJX02 (sarcandesartan sodium),
the method comprises the steps of taking a compound SAC04 prepared by the method as a raw material, treating the raw material with acid to obtain a compound YJX01, and reacting the compound YJX01 with VST in a first solvent in the presence of sodium hydroxide to prepare the compound YJX02.
In some embodiments, the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid. Compound SAC04 is more easily dissociated to obtain compound YJX01.
In some embodiments, the reaction to give compound YJX01 is where the reaction solvent is isopropyl acetate, or a mixed solvent of isopropyl acetate and water.
In some embodiments, the first solvent is acetone or a mixture of acetone and water.
In some embodiments, the reaction temperature for the reaction of the compound YJX01 with VST is 30 ℃ to 80 ℃.
In some embodiments, the reaction temperature for the reaction of the compound YJX01 with VST is 40 ℃ to 70 ℃.
In some embodiments, the reaction temperature for the reaction of the compound YJX01 with VST is 45 ℃ -65 ℃.
In a third aspect, the invention provides a preparation method of sarcandesartan sodium, which comprises a preparation method of a compound YJX02.
A method for preparing compound YJX02, comprising:
the compound S309A03 generates a compound BPA08 through hydrogenation, the compound BPA08 generates a compound SAC01 through reaction in ethanol, the compound SAC01 generates a compound SAC02 through reaction with succinic anhydride, and the compound SAC02 reacts with VST in a second solvent and in the presence of sodium hydroxide to prepare a compound YJX02.
In some embodiments, at least one of compound BPA08, compound SAC01, and compound SAC02 produced by the reaction is used directly in the next reaction without purification and/or drying.
In some embodiments, the compound BPA08 and/or compound SAC01 produced by the reaction is used directly in the next reaction without purification and/or drying. In some embodiments, the compound BPA08 and compound SAC01 produced by the reaction are directly used in the next reaction without purification and/or drying, which is beneficial to the acquisition of the target product.
In some embodiments, the compound SAC01 is reacted with succinic anhydride, wherein the content of ethanol in the solution of the compound SAC01 is 0.5% -10%, and the presence of ethanol is advantageous for removing the following impurities generated by the reaction:
in some embodiments, the compound SAC01 is reacted with succinic anhydride, wherein the ethanol content of the solution of the compound SAC01 is 1% -8%, which is more beneficial to removing impurities generated by the reaction.
In some embodiments, the solvent in which the compound SAC01 reacts with succinic anhydride is at least one of isopropyl acetate, methylene chloride, toluene, ethyl acetate, methyltetrahydrofuran, butyl acetate, t-butyl acetate, methyl t-butyl ether.
In some embodiments, the solvent for the hydrogenation reaction is ethanol, which is advantageous for obtaining the higher purity compound BPA08.
In some embodiments, the reaction temperature of the hydrogenation reaction is from 45 ℃ to 100 ℃.
In some embodiments, the reaction temperature of the hydrogenation reaction is from 65 ℃ to 80 ℃.
In some embodiments, the solvent for the reaction of the compound SAC01 and the succinic anhydride is at least one of isopropyl acetate, dichloromethane, toluene, ethyl acetate, methyltetrahydrofuran, butyl acetate, tert-butyl acetate and methyl tert-butyl ether, which is favorable for obtaining the compound SAC02 with higher purity, has easily available reagents, low reaction cost and is favorable for improving reaction yield.
In some embodiments, the temperature at which the compound SAC01 reacts with succinic anhydride is 30 ℃ to 80 ℃. The reaction condition is mild, and the process cost is low.
In some embodiments, the temperature at which the compound SAC01 reacts with succinic anhydride is 50 ℃ to 60 ℃.
In some embodiments, the second solvent is acetone or a mixture of acetone and water. The reaction conditions are advantageous for obtaining high yields of the compound YJX02.
In some embodiments, the reaction temperature for the reaction of compound SAC02 with VST is 30 ℃ to 80 ℃.
In some embodiments, the reaction temperature for the reaction of compound SAC02 with VST is 40 ℃ to 70 ℃.
In some embodiments, the reaction temperature for the reaction of compound SAC02 with VST is 45 ℃ to 65 ℃.
According to the preparation method of sarcandra-sodium, disclosed by the invention, the purification or/and drying processes of the compound BPA08 and the compound SAC01 are removed, the operation is simplified, the time required by the process is shortened, the total yield of the process route is greatly improved, and unexpected technical effects are obtained. The preparation method controls the content of ethanol in the solution of the compound SAC01, so that impurities in the process are removed, and a product with higher purity is obtained. The process condition is mild, and the method is suitable for industrial amplification.
Definition of terms
In the description of the present invention, it should be understood that the terms "first," "second," and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound SAC04", "SAC04" and "compound represented by formula SAC04" mean the same compound.
Drawings
FIG. 1 shows a related substance detection pattern of the compound SAC04 prepared in example 1;
FIG. 2 shows a diastereoisomeric detection profile of compound SAC04 prepared from example 1;
FIG. 3 shows a related substance detection pattern of the compound SAC04 prepared in example 2;
FIG. 4 shows a diastereoisomeric detection profile of compound SAC04 prepared from example 2;
FIG. 5 shows a related-substance detection pattern of the compound SAC04 prepared in example 3;
FIG. 6 shows a diastereoisomeric detection profile of compound SAC04 prepared from example 3;
FIG. 7 shows a mass detection pattern of the compound YJX02 prepared in example 4;
FIG. 8 shows a mass detection pattern of the compound YJX02 prepared in example 8;
FIG. 9 shows a mass detection pattern of the compound YJX02 prepared in example 9;
FIG. 10 shows a mass detection pattern of the compound YJX02 prepared in example 10.
Detailed Description
In order that those skilled in the art may better understand the technical solution of the present invention, the present invention provides a part of preparation examples, and the following further discloses some non-limiting examples to further describe the present invention in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the invention, mmol represents millimoles, mol/L and N represent mol/L, h represents hours, g represents grams, ml represents milliliters, L represents liters, DEG C represents degrees Celsius, TLC represents thin layer chromatography, GC represents gas chromatography, HPLC represents high performance liquid chromatography, VST represents valsartan (valsartan), etOH represents ethanol, i-PrOAc represents isopropyl acetate, naOH represents sodium hydroxide, and Acetone represents Acetone; DIPEA represents diisopropylethylamine.
EXAMPLE 1 preparation of Compound SAC04
100mL of ethanol, ruthenium reagent and iron reagent were stirred in a single-necked flask at room temperature for 30min and stirred well. To the reaction vessel, a solution of S309A03 (50 g), ruthenium reagent (40 mg) and iron reagent (65 mg) and 400mL of ethanol were sequentially added. After three times of nitrogen replacement, three times of hydrogen replacement are carried out, the pressure of the hydrogen is charged to 3.0MPa, and the temperature is raised to 65-80 ℃ for reaction. After 24 hours of reaction, the heating and cooling are closed, and the obtained reaction solution of BPA08 is directly used for subsequent reaction.
The BPA08 solution is added into a 1L four-neck flask at room temperature at the room temperature, 18.64g of SOCl2 is added dropwise, the mixture is stirred at the temperature of 45 ℃ after being added dropwise, and the transition state product is detected to be less than 0.5 percent by HPLC, and the reaction is stopped. Distilling 400-420ml ethanol under reduced pressure at 50-60deg.C, adding isopropyl acetate (200 ml), continuously distilling under reduced pressure to obtain 200-220ml liquid, repeating the above distillation operation for 3 times, adding isopropyl acetate (450 ml), stirring, collecting supernatant, detecting GC until ethanol content is 3.0%, and cooling to room temperature to obtain SAC01 suspension for the next reaction.
15.01g of succinic anhydride is added into the SAC01 reaction solution at room temperature; cooling to 0-10deg.C, stirring, dripping 20.3g DIPEA, sampling after dripping for 6 hr, feeding HPLC detection material SAC01<0.5%, adding 250ml 5% citric acid aqueous solution into the reaction solution after reaction, separating, and collecting organic phase. The organic phase is washed once with 250ml of water. To the organic phase were added 625ml of 1% saline solution and 142ml of 5% sodium hydroxide solution, the ph=7.5 was adjusted, the aqueous phase was once washed with 200ml of isopropyl acetate, the organic solvent in the aqueous phase was removed by distillation under reduced pressure at 50 ℃, the aqueous phase was warmed to 85-95 ℃, 150ml of 5% calcium chloride solution was added dropwise, cooled to room temperature after completion of the dropwise addition, stirred and suction-filtered, and the cake was washed with 250ml of water to obtain 53.6g of compound SAC04. The yield was 95.5%, the HPLC purity was 99.21% and the total diastereomer content in the isomer HPLC was 1.80%.
EXAMPLE 2 preparation of Compound SAC04
100mL of ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a single-necked flask at room temperature for 30min, and stirred well. S309A03 (50 g), ruthenium reagent and iron reagent solution and 400mL ethanol were added sequentially to the reaction vessel. After three times of nitrogen replacement, three times of hydrogen replacement are carried out, the pressure of the hydrogen is charged to 3.0MPa, and the temperature is raised to 65-80 ℃ for reaction. After 24 hours of reaction, the heating and cooling are closed, and the reaction solution of BPA08 is obtained and is directly used for the subsequent reaction.
Adding the BPA08 solution into a 1L four-neck flask at room temperature at the room temperature of 27 ℃, dropwise adding 23.3g of SOCl2, after the completion of the dropwise adding, stirring at 65 ℃ and HPLC to detect that the transitional state product is less than 0.5%, stopping the reaction, distilling the reaction solution at 50-60 ℃ under reduced pressure until the reaction solution is dry, adding toluene (450 ml), heating at 75 ℃ to dissolve the solution, taking the reaction solution to detect GC, and cooling the obtained SAC01 solution to the room temperature, wherein the ethanol content is 4.0%, and directly using the reaction solution for the next reaction.
15.01g of succinic anhydride is added into the SAC01 reaction solution at room temperature; stirring at room temperature, dropping 20.3g DIPEA, sampling after dropping for 6 hours, adding 250ml 5% citric acid aqueous solution to the reaction solution after HPLC reaction, separating, and collecting organic phase. The organic phase is washed once with 250ml of water. After the organic phase was distilled to dryness under reduced pressure at 50 ℃, isopropyl acetate (450 ml) was added, the solution was stirred and cooled to room temperature, and 625ml of 1% saline and 142ml of 5% sodium hydroxide solution were added to the organic phase to adjust ph=7.5. Separating, washing the water phase once with 200ml isopropyl acetate, distilling under reduced pressure at 50 ℃ to remove the organic solvent in the water phase, heating the water phase to 85-95 ℃, dropwise adding 150ml 5% calcium chloride solution, cooling to room temperature after dropwise adding, stirring, filtering, washing the filter cake with 250ml water, and drying in vacuum to obtain 53.0g compound SAC04. The yield was 95.5%, the purity of the product in the relevant material was 99.04%, and the total diastereomer content in the isomer HPLC was 0.07%.
EXAMPLE 3 preparation of Compound SAC04
100mL of ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a single-necked flask at room temperature for 30min, and stirred well. S309A03 (50 g), ruthenium reagent and iron reagent solution and 400mL ethanol were added sequentially to the reaction vessel. After three times of nitrogen replacement, three times of hydrogen replacement are carried out, the pressure of the hydrogen is charged to 3.0MPa, and the temperature is raised to 65-80 ℃ for reaction. After 24 hours of reaction, the heating and cooling are closed, and the reaction solution of BPA08 is obtained and is directly used for the subsequent reaction.
The BPA08 solution is added into a 1L four-neck flask at room temperature at the room temperature of 27 ℃, 23.3g of SOCl2 is added dropwise, the mixture is stirred for 1h at the temperature of 65 ℃ after the completion of the dripping, sampling is carried out, and the transition state product is detected to be less than 0.5% by HPLC, thus the reaction is completed. Distilling at 50-60deg.C under reduced pressure to dry, adding dichloromethane (450 ml), heating at 50deg.C to dissolve, sampling, inspecting to obtain SAC01 solution with GC ethanol content of 5.0%, and cooling to room temperature for the next reaction.
15.01g of succinic anhydride is added into the SAC01 reaction solution at room temperature; stirring at room temperature, dripping 20.3g of DIPEA, sampling after dripping for 6 hours, and carrying out HPLC detection on SAC <0.5%, wherein the reaction is completed. 250ml of 5% aqueous citric acid solution was added to the reaction mixture, and the mixture was separated to obtain an organic phase. The organic phase is washed once with 250ml of water. After the organic phase was distilled to dryness under reduced pressure at 50 ℃, 450ml of isopropyl acetate was added, the solution was stirred and cooled to room temperature, and 625ml of 1% saline and 142ml of 5% sodium hydroxide solution were added to the organic phase to adjust ph=7.5. Separating, washing the water phase once with 200ml isopropyl acetate, distilling under reduced pressure at 50 ℃ to remove the organic solvent in the water phase, heating the water phase to 85-95 ℃, dropwise adding 150ml 5% calcium chloride solution, cooling to room temperature after dropwise adding, stirring, filtering, and washing the filter cake with 250ml water to obtain 54.2g compound SAC04. The yield was 94.6%, the purity of the product in the relevant material was 99.25%, and the total diastereomer content in the isomer HPLC was 1.62%.
EXAMPLE 4 preparation of Compound YJX02
The reaction formula is as follows:
50g of SAC04, 500ml of isopropyl acetate and 300ml of water were added to the flask at room temperature, and stirred at room temperature, followed by 80.9g of 6% HCl solution, and the white solid in the flask gradually decreased until dissolved. The organic phase was separated and washed twice with 250ml of 5% citric acid, and the organic phase obtained after separation was washed twice with 250ml of water. The organic phase obtained was distilled under reduced pressure at 50℃until no significant fraction was obtained, and then distilled under reduced pressure for 4 hours. 500ml of acetone and 50.6g of VST were added to the flask, and after stirring and dissolving, 1.5g of activated carbon was added and stirred at room temperature for 0.5h, the mixture was suction-filtered to obtain a lower filtrate. 29.3g of 46% NaOH solution was then added dropwise to the flask. The flask was left to stir at 45℃for 1h, then the heating was stopped, slowly cooled to room temperature, 500ml of acetone was added dropwise, and stirring was continued at room temperature for 2h after the completion of the dropwise addition. Suction filtration, filter cake acetone washing (150 ml), and vacuum drying at 65℃gave 100.2g of white solid YJX02. The yield thereof was found to be 90.05%. The total yield from S309A03 to YJX02 was 85.99%, the total diastereomer content in the resulting product was 0.06%, the enantiomer content was 0, and the unspecified single impurity was < 0.10%.
EXAMPLE 5 preparation of Compound SAC02
100mL of chromatographic ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a single-necked flask at room temperature for 30min and stirred well. S309A03 (50 g), ruthenium reagent and iron reagent solution and 400mL ethanol were added sequentially to the reaction vessel. After three times of nitrogen replacement, three times of hydrogen replacement are carried out, the pressure of the hydrogen is charged to 3.0MPa, and the temperature is raised to 65-80 ℃ for reaction. After 24 hours of reaction, the heating and cooling are closed, and the reaction solution of BPA08 is obtained and directly used for the subsequent reaction without purification.
The BPA08 solution is added into a 1L four-neck flask at room temperature and the temperature is 27 ℃, 18.64g of SOCl is added dropwise 2 After the dripping, stirring at 45 ℃ for 4 hours, sampling, and sending to HPLC, when the transition state product<And (3) distilling 400-420ml of ethanol at 50-60 ℃ under reduced pressure after the reaction is qualified when 0.5% is qualified, adding isopropyl acetate (200 ml), continuously distilling under reduced pressure until 200-220ml of liquid is distilled under reduced pressure, repeating the reduced pressure distillation operation for 3 times, adding isopropyl acetate (450 ml), uniformly stirring, taking supernatant liquid, detecting GC, and cooling the obtained SAC01 suspension to room temperature, and directly using the SAC01 suspension for the next reaction.
15.01g of succinic anhydride is added into the SAC01 reaction solution at room temperature; stirring at room temperature, dripping 20.3g DIPEA, sampling after dripping for 6h, feeding HPLC, reacting until SAC01<0.5%, adding 250ml 5% citric acid aqueous solution into the reaction solution after the reaction, separating, and collecting organic phase. The organic phase was washed twice with 250ml of water to prepare a solution of compound SAC02 for use.
EXAMPLE 6 preparation of Compound SAC02
100mL of chromatographic ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a single-necked flask at room temperature for 30min and stirred well. S309A03 (50 g), ruthenium reagent and iron reagent solution and 400mL ethanol were added sequentially to the reaction vessel. After three times of nitrogen replacement, three times of hydrogen replacement are carried out, the pressure of the hydrogen is charged to 3.0MPa, and the temperature is raised to 65-80 ℃ for reaction. After 24 hours of reaction, the heating and cooling are closed, and the reaction solution of BPA08 is obtained and directly used for the subsequent reaction without purification.
Adding the BPA08 solution into a 1L four-neck flask at room temperature at the room temperature of 27 ℃, dropwise adding 23.3g of SOCl2, stirring for 1h at the temperature of 65 ℃ after the dropwise adding, sampling, sending HPLC, carrying out reduced pressure distillation at the temperature of 50-60 ℃ until the reaction is qualified after the transition state product is less than 0.5%, adding toluene (450 ml) after the reaction is qualified, heating the solution at the temperature of 75 ℃ for clearing, detecting GC, and detecting the ethanol content to 3.5%, wherein the obtained SAC01 solution is cooled to the room temperature and directly used for the next reaction.
15.01g of succinic anhydride is added into the SAC01 reaction solution at room temperature; stirring at room temperature, dripping 20.3g DIPEA, sampling after dripping for 6h, feeding HPLC, allowing SAC01<0.5% to react, adding 250ml 5% citric acid aqueous solution into the reaction solution after the reaction, separating, and collecting organic phase. The organic phase is washed twice with 250ml of water and is ready for use.
EXAMPLE 7 preparation of Compound SAC02
100mL of chromatographic ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a single-necked flask at room temperature for 30min and stirred well. S309A03 (50 g), ruthenium reagent and iron reagent solution and 400mL ethanol were added sequentially to the reaction vessel. After three times of nitrogen replacement, three times of hydrogen replacement are carried out, the pressure of the hydrogen is charged to 3.0MPa, and the temperature is raised to 65-80 ℃ for reaction. After 24 hours of reaction, the heating and cooling are closed, and the reaction solution of BPA08 is obtained and directly used for the subsequent reaction without purification.
The BPA08 solution is added into a 1L four-neck flask at room temperature and the temperature of 27 ℃ at room temperature, and 23.3g of SOCl is added dropwise 2 After the dripping, stirring for 1h at 65 ℃, sampling, and sending HPLC to the transition state product<And if 0.5 percent of the reaction is qualified, and if the reaction is qualified, the reaction is finished. Vacuum steaming at 50-60deg.CAfter distillation to dryness, DCM (450 ml) was added, and after heating the solution at 50deg.C, the GC ethanol content was checked for 4.2% and the resulting SAC01 solution was cooled to room temperature and used directly in the next reaction.
15.01g of succinic anhydride is added into the SAC01 reaction solution at room temperature; stirring at room temperature, dripping 20.3g DIPEA, sampling after dripping for 6h, feeding HPLC, allowing SAC01<0.5% to react, adding 250ml 5% citric acid aqueous solution into the reaction solution after the reaction, separating, and collecting organic phase. The organic phase is washed twice with 250ml of water and is ready for use.
EXAMPLE 8 preparation of Compound YJX02
After the content of SAC02 solution obtained in example 5 was detected by the external standard method, the obtained organic phase was distilled under reduced pressure at 50℃until no significant fraction was present, and then distilled under reduced pressure was continued for 4 hours. 500ml of acetone and 50.6g of VST were added to the flask, and after stirring and dissolving, 1.5g of activated carbon was added and stirred at room temperature for 0.5h, the mixture was suction-filtered to obtain a lower filtrate. 29.3g of 46% NaOH solution was then added dropwise to the flask. The flask was left to stir at 45℃for 1h, then the heating was stopped, slowly cooled to room temperature, 500ml of acetone was added dropwise, and stirring was continued at room temperature for 2h after the completion of the dropwise addition. Suction filtration, filter cake acetone washing (150 ml), and vacuum drying at 65℃gave 100.5g of white solid YJX02. The total yield from S309a03 to YJX02 was 84.9%, purity >99.8% and impurity D was 0.13%.
EXAMPLE 9 preparation of Compound YJX02
After the content of the SAC02 solution obtained in example 6 was detected by the external standard method, the obtained organic phase was distilled under reduced pressure at 50℃until no significant fraction was obtained, and then distillation under reduced pressure was continued for 4 hours, 200ml of acetone was added to the flask, and distillation under reduced pressure was continued again until no significant fraction was obtained, and then distillation under reduced pressure was continued for 4 hours. 500ml of acetone and 50.6g of VST were added to the flask, and after stirring and dissolving, 1.5g of activated carbon was added and stirred at room temperature for 0.5h, the mixture was suction-filtered to obtain a lower filtrate. 29.3g of 46% NaOH solution was then added dropwise to the flask. The flask was left to stir at 45℃for 1h, then the heating was stopped, slowly cooled to room temperature, 500ml of acetone was added dropwise, and stirring was continued at room temperature for 2h after the completion of the dropwise addition. Suction filtration, filter cake acetone washing (150 ml), and vacuum drying at 65℃gave 99.8g of white solid YJX02. The total yield from S309a03 to YJX02 was 81.5%, purity >99.5%, and impurity D was not detected.
EXAMPLE 10 preparation of Compound YJX02
After the content of the SAC02 solution obtained in example 7 was detected by the external standard method, the obtained organic phase was distilled under reduced pressure at 50℃until no significant fraction was obtained, and then distillation under reduced pressure was continued for 4 hours, 200ml of acetone was added to the flask, and distillation under reduced pressure was continued again until no significant fraction was obtained, and then distillation under reduced pressure was continued for 4 hours. 500ml of acetone and 50.6g of VST were added to the flask, and after stirring and dissolving, 1.5g of activated carbon was added and stirred at room temperature for 0.5h, the mixture was suction-filtered to obtain a lower filtrate. 29.3g of 46% NaOH solution was then added dropwise to the flask. The flask was left to stir at 45℃for 1h, then the heating was stopped, slowly cooled to room temperature, 500ml of acetone was added dropwise, and stirring was continued at room temperature for 2h after the completion of the dropwise addition. Suction filtration, filter cake acetone washing (150 ml), and vacuum drying at 65℃gave 98.3g of white solid YJX02. The total yield from S309a03 to YJX02 was 80.8%, purity >99.5% and impurity D was 0.07%.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (8)
1. A method for preparing compound SAC04,
comprising the following steps: compound S309a03 is reacted by hydrogenation to produce compound BPA08, and compound BPA08 is reacted in ethanol to produce compound SAC01; further comprises: compound SAC01 reacts with succinic anhydride to generate compound SAC02, compound SAC02 reacts with sodium hydroxide to generate compound SAC03, compound SAC03 reacts with calcium chloride to generate compound SAC04;
it is characterized in that the method comprises the steps of,
the compound BPA08, the compound SAC01, the compound SAC02 and the compound SAC03 generated by the reaction are directly used for the next reaction without purification and drying; the solvents for the reaction of the compound SAC01 and succinic anhydride are isopropyl acetate, toluene, isopropyl acetate and methylene dichloride.
2. The process of claim 1, wherein the solvent for the hydrogenation reaction is ethanol.
3. A preparation method of a compound YJX02,
comprising, preparing compound SAC04 according to the method of claim 1, treating the obtained compound SAC04 as a raw material with acid to obtain compound YJX01, and reacting the compound YJX01 with valsartan in a first solvent and in the presence of sodium hydroxide to obtain compound YJX02.
4. A method according to claim 3, wherein the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid.
5. A method according to claim 3, wherein the first solvent is acetone or a mixture of acetone and water.
6. A preparation method of a compound YJX02,
comprising the following steps: the compound S309A03 generates a compound BPA08 through hydrogenation, the compound BPA08 generates a compound SAC01 through reaction in ethanol, the compound SAC01 generates a compound SAC02 through reaction with succinic anhydride, and the compound SAC02 reacts with valsartan in a second solvent and in the presence of sodium hydroxide to prepare a compound YJX02; it is characterized in that the method comprises the steps of,
the compound BPA08, the compound SAC01 and the compound SAC02 generated by the reaction are directly used for the next reaction without purification and drying; the solvents for the reaction of the compound SAC01 and succinic anhydride are isopropyl acetate, toluene, isopropyl acetate and methylene dichloride.
7. The method of claim 1 or 6, wherein the compound SAC01 is reacted with succinic anhydride, wherein the ethanol content of the solution of the compound SAC01 is 1% -8%.
8. The method of claim 7, wherein the second solvent is acetone or a mixture of acetone and water.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910942858.2A CN112574132B (en) | 2019-09-30 | 2019-09-30 | Preparation method of sarcandra/valsartan sodium |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910942858.2A CN112574132B (en) | 2019-09-30 | 2019-09-30 | Preparation method of sarcandra/valsartan sodium |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112574132A CN112574132A (en) | 2021-03-30 |
CN112574132B true CN112574132B (en) | 2024-02-27 |
Family
ID=75116458
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910942858.2A Active CN112574132B (en) | 2019-09-30 | 2019-09-30 | Preparation method of sarcandra/valsartan sodium |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112574132B (en) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药(湖北)有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
CN105330609A (en) * | 2015-12-07 | 2016-02-17 | 南京正大天晴制药有限公司 | Method for preparing LCZ696 |
CN105985225A (en) * | 2015-02-12 | 2016-10-05 | 博瑞生物医药(苏州)股份有限公司 | Preparation methods for LCZ-696 and intermediate thereof |
WO2017020841A1 (en) * | 2015-08-03 | 2017-02-09 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing lcz696 and preparation method thereof |
CN106905253A (en) * | 2015-12-23 | 2017-06-30 | 正大天晴药业集团股份有限公司 | A kind of crystallization of supramolecular complex |
CN107033094A (en) * | 2016-02-04 | 2017-08-11 | 南京卡文迪许生物工程技术有限公司 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
CN108373423A (en) * | 2018-04-28 | 2018-08-07 | 成都苑东生物制药股份有限公司 | Preparation method of the one planting sand library than bent Valsartan compound and/or eutectic key intermediate sand library than bent calcium |
-
2019
- 2019-09-30 CN CN201910942858.2A patent/CN112574132B/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
CN105985225A (en) * | 2015-02-12 | 2016-10-05 | 博瑞生物医药(苏州)股份有限公司 | Preparation methods for LCZ-696 and intermediate thereof |
WO2017020841A1 (en) * | 2015-08-03 | 2017-02-09 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing lcz696 and preparation method thereof |
CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药(湖北)有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
CN105330609A (en) * | 2015-12-07 | 2016-02-17 | 南京正大天晴制药有限公司 | Method for preparing LCZ696 |
CN106905253A (en) * | 2015-12-23 | 2017-06-30 | 正大天晴药业集团股份有限公司 | A kind of crystallization of supramolecular complex |
CN107033094A (en) * | 2016-02-04 | 2017-08-11 | 南京卡文迪许生物工程技术有限公司 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
CN108373423A (en) * | 2018-04-28 | 2018-08-07 | 成都苑东生物制药股份有限公司 | Preparation method of the one planting sand library than bent Valsartan compound and/or eutectic key intermediate sand library than bent calcium |
Also Published As
Publication number | Publication date |
---|---|
CN112574132A (en) | 2021-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108675943A (en) | The preparation method of one planting sand library Ba Qu key intermediates | |
WO2014020555A2 (en) | An improved process for the preparation of dabigatran etexilate mesylate | |
CN112079742B (en) | Method for preparing lidocaine through continuous reaction | |
CN114014787A (en) | Asymmetric synthesis method for preparing (2S,3R) -p-methylsulfonylphenylserine ethyl ester | |
CN102746288B (en) | Preparation methods of anticoagulant and key intermediate of anticoagulant | |
KR101250820B1 (en) | An improved process for the preparation of losartan | |
CN108440409B (en) | Green and efficient preparation method of rebamipide | |
CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
CN114621068A (en) | Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin | |
CN112574132B (en) | Preparation method of sarcandra/valsartan sodium | |
CN111205216A (en) | Method for preparing saxagliptin | |
EP2417110B1 (en) | A one pot process for preparing 2-butyl-3-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro [4, 4]non-1-en-4-one (irbesartan) | |
CN111393329A (en) | Preparation method of ritonavir and lopinavir intermediate | |
CN107674026B (en) | Preparation method of ruxolitinib intermediate (3R) -3- (4-bromo-1H-pyrazol-1-yl) -cyclopentyl propionitrile | |
SK50932005A3 (en) | Method for the preparation of N-(1-oxopentyl)-N-[[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine (valsartan) | |
WO2006080401A1 (en) | Method for producing fluorinated proline derivative | |
CN104326927B (en) | A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate | |
CN114315679A (en) | Preparation method of Upactinib chiral intermediate | |
CN112174798A (en) | Synthesis method of Sacubitril valsartan sodium LCZ696 | |
CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
CN105732613B (en) | A kind of synthetic method of 9 demethyl (+) α dihydrotetrabenazineins | |
CN117402118A (en) | Preparation method of rosuvastatin calcium intermediate | |
CN111018734B (en) | Synthesis method of cinacalcet hydrochloride intermediate | |
CN111362824B (en) | Process for the preparation of 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide and salts thereof | |
CN110835319B (en) | Synthesis method of benazepril intermediate and benazepril hydrochloride |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Applicant after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Applicant before: SUNSHINE LAKE PHARMA Co.,Ltd. |
|
CB02 | Change of applicant information | ||
GR01 | Patent grant | ||
GR01 | Patent grant |